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A Novel Antibody Engineering Strategy for Making Monovalent Bispecific Heterodimeric IgG Antibodies by Electrostatic Steering Mechanism
Authors:Zhi Liu  Esther C. Leng  Kannan Gunasekaran  Martin Pentony  Min Shen  Monique Howard  Janelle Stoops  Kathy Manchulenko  Vladimir Razinkov  Hua Liu  William Fanslow  Zhonghua Hu  Nancy Sun  Haruki Hasegawa  Rutilio Clark  Ian N. Foltz  Wei Yan
Affiliation:From the Departments of Therapeutic Discovery and ;**Process and Product Development, ;‡‡Therapeutic Innovation Unit, ;§Amgen Inc., Seattle, Washington 98119, ;Amgen Inc., Thousand Oaks, California 91320, and ;Amgen Inc., Burnaby, British Columbia V5A 1V7, Canada
Abstract:Producing pure and well behaved bispecific antibodies (bsAbs) on a large scale for preclinical and clinical testing is a challenging task. Here, we describe a new strategy for making monovalent bispecific heterodimeric IgG antibodies in mammalian cells. We applied an electrostatic steering mechanism to engineer antibody light chain-heavy chain (LC-HC) interface residues in such a way that each LC strongly favors its cognate HC when two different HCs and two different LCs are co-expressed in the same cell to assemble a functional bispecific antibody. We produced heterodimeric IgGs from transiently and stably transfected mammalian cells. The engineered heterodimeric IgG molecules maintain the overall IgG structure with correct LC-HC pairings, bind to two different antigens with comparable affinity when compared with their parental antibodies, and retain the functionality of parental antibodies in biological assays. In addition, the bispecific heterodimeric IgG derived from anti-HER2 and anti-EGF receptor (EGFR) antibody was shown to induce a higher level of receptor internalization than the combination of two parental antibodies. Mouse xenograft BxPC-3, Panc-1, and Calu-3 human tumor models showed that the heterodimeric IgGs strongly inhibited tumor growth. The described approach can be used to generate tools from two pre-existent antibodies and explore the potential of bispecific antibodies. The asymmetrically engineered Fc variants for antibody-dependent cellular cytotoxicity enhancement could be embedded in monovalent bispecific heterodimeric IgG to make best-in-class therapeutic antibodies.
Keywords:Antibody, Antibody Engineering, Cancer Therapy, Fc-γ   Receptor, Pancreatic Cancer
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